The invention herein describes a method of facilitating the entry of drugs into cells at pharmokinetically useful levels and also a method of targeting drugs to specific organelles within the cell. This lipid/drug conjugate targeting invention embodies an advance over other drug targeting methods because through this method, intracellular drug concentrations may reach levels which are orders of magnitude higher than those achieved otherwise. Furthermore, it refines the drug delivery process by allowing therapeutic agents to be directed to certain intracellular structures. This technology is appropriate for use with antiviral and antineoplastic drugs because it has been observed that both virally infected and neoplastic cells have an altered intracellular organelle morphology.
Numerous methods for enhancing the activity and specificity of antiviral and antineoplastic drug action have been proposed. In general, the desired result is to increase both the efficiency and specificity of the therapeutic agent. One method of achieving this result has been receptor targeting. This method involves linking the therapeutic agent to a ligand which has an affinity for a receptor expressed on the desired target cell. Treatment by this method results in the drug adhering to the target cell through the ligand receptor complex and exerting its therapeutic effects directly on the cell.
One drawback of receptor targeting lies in the finite number of receptors on target cells. It has been estimated that the maximum number of receptors on a cell is approximately one million (Darnell, Lodish and Baltimore, Molecular Cell Biology (1986)). Thus, there is a maximum binding of one million drug ligand complexes to any given cell. Furthermore, the maximum number of specific receptors is much lower, for example, for a specific steroid, there are between ten thousand and one hundred thousand. Id. Thus, attempts at receptor targeting wherein the drug is conjugated with a ligand specific for a single receptor type will result in a maximum binding of less than about one hundred thousand conjugates per cell.
In response to the deficiencies encountered with receptor targeting, investigators have looked for other methods of delivering therapeutic agents at concentrations higher than those achievable through the receptor targeting process. Experiments suggested that lipids have selective affinities for specific biological membranes.
The selective association of certain lipids with specific biological membranes provided a possible avenue of drug targeting. In light of this possibility, researchers have attempted to target drugs by conjugating them with cholesterol. Unfortunately, these attempts have met with disappointing results. Remy et al., 1962, J. Org. Chem. 27:2491-2500. Mukhergee, K. L., Heidelberger, C., 1962, Cancer Research 22:815-22. Brewster, M. E., et al., Improved delivery through biological membranes. XXXL: Solubilization and stabilization of an estradiol chemical delivery system by modified beta-cyclodextrins, J. Pharm. Sci. 77:981-985, have had some success with carrying estradiol to the brain using pyridinium salts as carriers.
Another attempt at cell targeting through the use of lipids was made by Rahman et al., 1982, Life Sci. 31:2061-71. These investigators found that liposomes which contained galactolipid as part of the lipid appeared to have a higher affinity for parenchymal cells than liposomes which lacked galactolipid. These researchers suggested that this finding might have utility in drug targeting.
An additional challenge in designing an appropriate drug delivery scheme is to include within the drug conjugate a functionality which could either accelerate or reduce the rate at which the drug is released upon arrival at the desired site. Such a functionality would be especially valuable if it allowed differential rates of drug release.